Intercept Lung Cancer Through Immune, Imaging & Molecular Evaluation-InTIME – Part 2
Lung cancer is the leading cause of cancer death globally, primarily due to challenges in early detection. With funding from Stand Up to Cancer, LUNGevity Foundation, and the American Lung Association, a multidisciplinary team called the Lung Cancer Interception Dream Team was formed in 2017 to tackle this challenge, uniting expertise from various fields to enhance lung cancer interception and prevention.
This initiative includes the development of a lung pre-cancer genome atlas (PCGA) aimed at understanding molecular changes linked to the progression of pre-cancerous lesions to lung carcinoma. With continued funding from LUNGevity Foundation and the American Lung Association, the team plans to establish a temporal atlas for premalignant lung adenocarcinoma by utilizing robot-assisted bronchoscopy to collect samples from patients with ground glass opacities (GGOs) suspected of lung cancer. This effort will not only help identify these lesions but also facilitate the targeted delivery of intervention agents.
By gaining insights into progression-associated molecular alterations and cellular interactions, the team aims to significantly advance lung cancer interception strategies - catching cancer at its earliest stages and treatment it before it grows and spreads. Ultimately, the goal is to provide personalized interception approaches for individuals at risk of developing lung cancer.
- Research Summary
Cancer interception is catching cancer at its earliest stages and treatment it before it grows and spreads. Our current lack of effective lung cancer interception methods stems from an incomplete understanding of the early molecular events in lung cancer development, Through the 2017 Stand Up To Cancer – LUNGevity Foundation – American Lung Association grant, a multidisciplinary team called the Lung Cancer Interception Dream Team has established the Lung Pre-Cancer Genome Atlas (PCGA), identifying immune and epithelial changes linked to who normal cells become pre-malignant cancer cells. With a second round of funding from LUNGevity Foundation and the American Lung Association, the team will be building on these foundational findings and enhance their efforts by developing a temporal atlas of genomic (DNA-level changes), transcriptomic (RNA-level), and epigenetic changes in pre-malignant lung adenocarcinoma lesions through longitudinal sampling. The team hypothesizes that these lesions exhibit specific genomic, transcriptomic, and epigenetic alterations, with some evading immune detection and advancing to invasive cancer. Ultimately, the insights gained will provide valuable resources for the research community and significantly impact early-stage lung cancer interception.
- Technical Abstract
We lack effective lung cancer interception approaches due to our incomplete understanding of the earliest molecular events associated with lung carcinogenesis, which leave clinicians with few tools to manage precancerous lesions that may be found on CT screening. Our multidisciplinary Lung Cancer Interception Dream Team has made significant progress in establishing a Lung Pre-Cancer Genome Atlas(PCGA) where we have begun to identify immune and epithelial alterations associated with premalignant disease progression. To extend our findings in order to refine targets for lung cancer interception trials, we are proposing to extend our on-going PCGA efforts with two important aims 1) Develop a temporal atlas of premalignant lung adenocarcinoma via establishment of a cohort of longitudinally-sampled ground glass opacities (GGOs) collected with robot-assisted bronchoscopy, representing premalignant and minimally-invasive lung adenocarcinomas and 2) based on our current findings and feedback from our previous reviewers, we will expand our profiling to include spatial and epigenetic profiling of precancerous lesions and minimally invasive carcinoma in biopsy samples collected from the GGO cohort and our Pre-Cancer Genome Atlas 2.0 cohorts. We hypothesize that premalignant lesions bear specific genomic, transcriptomic and epigenetic aberrations, and a subset of these lesions escape immune surveillance and progress to invasive cancer. Our team, will apply spatial profiling using imaging mass cytometry and spatial transcriptomics will allow us to uncover the tissue architecture of the molecular processes associated with progression which in turn will help delineate the cell-cell interactions underlying these processes. Epigenetic profiling via single cell ATAC and bulk DNA methylation sequencing will allow us to overlay information about transcriptional regulation with the other ‘omic data to better understand the regulation of processes associated with progression. Critical to the success of the proposal is the multidisciplinary expertise of the team, involvement of patient advocates and the extensive preliminary data supporting the feasibility of the proposed approaches. The insights gained from successful completion of this project and the data that will made available to the research community will serve as a foundational resource for other investigators in the field and will result in a significant and sustained impact on the interception of early-stage lung cancers.